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EP-3600411-B1 - ANTIBODIES FOR THE TREATMENT OF ERBB-2/ERBB-3 POSITIVE TUMORS

EP3600411B1EP 3600411 B1EP3600411 B1EP 3600411B1EP-3600411-B1

Inventors

  • THROSBY, MARK
  • GEUIJEN, CECILIA ANNA WILHELMINA
  • MAUSSANG-DETAILLE, DAVID ANDRE BAPTISTE
  • LOGTENBERG, TON

Dates

Publication Date
20260506
Application Date
20180403

Claims (10)

  1. A bispecific afucosylated antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3 for use in the treatment of an ErbB-2/ErbB-3 positive tumor in a human subject, which subject has not previously been treated with an ErbB-2 specific therapy or with an ErbB-3 specific therapy, wherein said ErbB-2/ErbB-3 positive tumor has a ratio of ErbB-2/ErbB-3 cell-surface receptors per cell of at least 10:1, wherein said first antigen-binding site that binds ErbB-2 comprises the heavy chain sequence the second antigen-binding site that binds ErbB-3 comprises the heavy chain sequence wherein said first antigen-binding site and said second-antigen binding site comprise the light chain sequence
  2. The bispecific antibody for use according to claim 1, wherein said ErbB-2/ErbB-3 positive tumor has a ratio of ErbB-2/ErbB-3 cell-surface receptors per cell of at least 100:1.
  3. The bispecific antibody for use according to claim 1 or 2, wherein said ErbB-2/ErbB-3 positive tumor is classified as either ErbB-2 ++ or ErbB-2 +++.
  4. A bispecific afucosylated antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3 for use in the treatment of an ErbB-2/ErbB-3 positive tumor in a human subject, which subject has not previously been treated with an ErbB-2 specific therapy, wherein said ErbB-2/ErbB-3 positive tumor is classified as ErbB-2 +++, wherein said first antigen-binding site that binds ErbB-2 comprises the heavy chain sequence the second antigen-binding site that binds ErbB-3 comprises the heavy chain sequence and wherein said first antigen-binding site and said second antigen binding site comprise the light chain sequence
  5. The bispecific antibody for use according to any one of the preceding claims, wherein said ErbB-2/ErbB-3 positive tumor has less than 50,000 ErbB-3 cell-surface receptors per cell.
  6. The bispecific antibody for use according to any one of the preceding claims, wherein the ErbB-1 cell-surface receptor density, ErbB-2 cell-surface receptor density, and/or ErbB-3 cell-surface receptor density for said tumor is determined.
  7. The bispecific antibody for use according to claim 6, wherein the ErbB-2/ErbB-3 positive tumor has a ratio of ErbB-1/ErbB-2 cell-surface receptors per cell of no more than 6:10.
  8. The bispecific antibody for use according to any one of the preceding claims, wherein the ErbB-2/ErbB-3 positive tumor is a breast cancer, gastric cancer, colorectal cancer, colon cancer, gastro-esophageal cancer, esophageal cancer, endometrial cancer, ovarian cancer, liver cancer, lung cancer including non-small cell lung cancer, clear cell sarcoma, salivary gland cancer, head and neck cancer, brain cancer, bladder cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, or melanoma.
  9. The bispecific antibody for use according to any one of the preceding claims, wherein the ErbB-2/ErbB-3 positive tumor is a breast cancer.
  10. The bispecific antibody for use according to any one of the preceding claims, wherein said treatment further comprises the use of an ErbB-1 inhibitor for treating said tumor.

Description

This application claims priority to EP Application No. 17164382.8, filed March 31, 2017 The invention relates to the field of antibodies. In particular it relates to the field of therapeutic (human) antibodies for the treatment of ErbB-2/ErbB-3 positive tumor. More in particular it relates to treating tumors with a high ErbB-2/ErbB-3 cell-surface receptor ratio in patients not previously treated with an ErbB-2 specific therapy or with a ErbB-3 specific therapy. The human epidermal growth factor receptor family (HER, also collectively referred to as the ErbB signaling network) is a family of transmembrane receptor tyrosine kinases (RTK). The family includes the epidermal growth factor receptor (EGFR), also known as ErbB-1 (or HERl), and the homologous receptors ErbB-2 (HER2), ErbB-3 (HER3) and ErbB-4 (HER4). The receptors (reviewed in Yarden and Pines 2012) are widely expressed on epithelial cells. Upregulation of HER receptors or their ligands, such as heregulin (HRG) or epidermal growth factor (EGF), is a frequent event in human cancer (Wilson, Fridlyand et al. 2012). Overexpression of ErbB-1 and ErbB-2 in particular occurs in epithelial tumors and is associated with tumor invasion, metastasis, resistance to chemotherapy, and poor prognosis (Zhang, Berezov et al. 2007). In the normal breast, ErbB-3 has been shown to be important in the growth and differentiation of luminal epithelium. For instance, loss/inhibition of ErbB-3 results in selective expansion of the basal over the luminal epithelium (Balko, Miller et al. 2012). Binding of ligand to the extracellular domain of the RTKs induces receptor dimerization, both between the same (homodimerization) and different (heterodimerization) receptor subtypes. Dimerization can activate the intracellular tyrosine kinase domains, which undergo autophosphorylation and, in turn, can activate a number of downstream pro-proliferative signaling pathways, including those mediated by mitogen-activated protein kinases (MAPK) and the prosurvival pathway Akt (reviewed in Yarden and Pines, 2012). No specific endogenous ligand has been identified for ErbB-2, which is therefore assumed to normally signal through heterodimerization (Sergina, Rausch et al. 2007). ErbB-3 can be activated by engagement of its ligands. These ligands include but are not limited to neuregulin (NRG) and heregulin (HRG). Various modes of activation of signaling of the ErbB receptor family have been identified. Among these are ligand dependent and ligand independent activation of signaling. Over-expressed ErbB-2 is able to generate oncogenic signaling through the ErbB-2:ErbB-3 heterodimer even in the absence of the ErbB-3 ligand (Junttila, Akita et al. 2009). ErbB-2 activity can be inhibited by ErbB-2 specific antibodies. Such ErbB-2 specific antibodies are for instance used in the treatment of ErbB-2 positive (HER2+) tumors. A problem with such treatments is that often tumors escape the ErbB-2 specific treatment and continue to grow even in the presence of the inhibiting antibody. It has been observed that ErbB-2 positive tumors, such as breast, ovarian, cervical and gastric tumors can escape treatment by the selective outgrowth of a subpopulation of tumor cells that exhibit upregulated ErbB-3 expression (Ocana, Vera-Badillo et al. 2013) and/or ErbB-3 ligand expression (Wilson, Fridlyand et al. 2012). Also activating mutations in the ErbB-3 receptor have been identified. SUMMARY OF THE INVENTION The present invention is provided in the appended set of claims. The invention provides a bispecific afucosylated antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3 for use in the treatment of an ErbB-2/ErbB-3 positive tumor in a human subject, which subject has not previously been treated with an ErbB-2 specific therapy or with an ErbB-3 specific therapy, wherein said ErbB-2/ErbB-3 positive tumor has a ratio of ErbB-2/ErbB-3 cell-surface receptors per cell of at least 10:1,wherein said first antigen-binding site that binds ErbB-2 comprises the heavy chain sequence the second antigen-binding site that binds ErbB-3 comprises the heavy chain sequence wherein said first antigen-binding site and said second-antigen binding site comprise the light chain sequence The invention also provides a bispecific afucosylated antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3 for use in the treatment of an ErbB-2/ErbB-3 positive tumor in a human subject, which subject has not previously been treated with an ErbB-2 specific therapy, wherein said ErbB-2/ErbB-3 positive tumor is classified as ErbB-2 +++,wherein said first antigen-binding site that binds ErbB-2 comprises the heavy chain sequence the second antigen-binding site that binds ErbB-3 comprises the heavy chain sequence andwherein said first antigen-binding site and said second antigen binding site comprise the light chain sequence In o